Poster Presentation 6th Australian Health and Medical Research Congress 2012

Sphingosine kinase-1 regulates adhesion molecule expression for neutrophil trafficking during allergic inflammation (#328)

Wai Yan (Kiwi) Sun 1 2 3 , Latasha Abeynaike 4 , Stuart Pitson 1 5 , Michael Hickey 4 , Claudine S Bonder 1 2 3
  1. Centre for Cancer Biology, SA Pathology, Adelaide, SA , Australia
  2. School of Medicine, The University of Adelaide, Adelaide, Australia
  3. CRC for Biomarker Translation, La Trobe University, Victoria, Australia
  4. Centre for Inflammatory Diseases, Dept of Medicine, Monash Medical Centre, Melbourne, Victoria, Australia
  5. School of Biochemistry, The University of Adelaide, Adelaide, Australia

Rapid recruitment of neutrophils to a site of inflammation is associated with allergic diseases, such as asthma and anaphylaxis. Although anti-histamines and steroids are the mainstay of treatment for symptomatic relief, their effectiveness is varied as the current health costs for allergy are still more than $7 billion yearly. Thus, a better understanding of acute allergic reactions is required.

The classical paradigm for cell recruitment suggests that selectins, integrins and cellular adhesion molecules stabilize the rolling neutrophils to the endothelium enabling adhesion and emigration from the vasculature. P-selectin is an adhesion molecule that is stored in Weibel Palade bodies of vascular endothelial cells (ECs) and is rapidly exocytosed to the cell surface upon histamine stimulation for the recruitment of neutrophils. Thus, investigation of the mechanism for P-selectin regulating neutrophil recruitment may provide the key to controlling acute inflammation.

This study examines a role of sphingosine kinase (SK) mediated P-selectin expression on ECs for the rapid recruitment of neutrophils. SK is a highly conserved lipid kinase and ubiquitously expressed at varying levels in different cell types which catalyses the phosphorylation of sphingosine to form sphingosine-1-phosphate. We have identified that histamine induced P-selectin expression on human umbilical vein ECs requires SK activity and regulates neutrophil rolling along the vasculature in vitro and in vivo. In addition, administration of FTY720 (the only FDA approved oral drug for the treatment of multiple sclerosis) attenuates histamine-induced neutrophil recruitment. Different routes of local administration can also decrease histamine-induced inflammatory responses over time.

Overall, this study proposes that SK maybe a target for developing new therapeutics for the prevention and treatment of excessive neutrophil recruitment during inflammation which results in acute and fatal anaphylaxis.